The role of gut microbes in ADHD
The takeaway:
Attention deficit disorder (ADHD) is primarily determined by genetics, but several environmental factors play a role, including gut microbiota and factors that influence gut microbiota
Perinatal risk factors can increase the risk of ADHD, including preterm birth, infant stress, Caesarean section, and maternal infection, obesity and stress
Although gut microbiota are expected to influence ADHD, differences in gut microbiota in individuals with ADHD remains unclear
Dietary and probiotic interventions may improve ADHD outcomes
Read on for more!
ADHD has a high level of heritability, demonstrated by family, adoption and twin studies. Biological siblings have a 2-8 fold increased risk of ADHD compared with adoptive relatives [1]. Studies of monozygotic twins have shown that ADHD is about 80% genetic, which means that environmental factors play a role of about 20% [2]. Several environmental risk factors for ADHD have been explored; in this post, I’ll discuss the relationship between gut microbiota and ADHD and how perturbations in gut microbiota may influence the development of ADHD.
In the context of mental health, the proposed mechanisms by which the gut microbiota may modulate brain development, cognitive function and behavior include immune, metabolic, endocrine, and neural pathways [3]. Unfortunately, the exact factors that lead to ADHD are unknown, but deficits in the neurotransmitters dopamine, noradrenaline and serotonin play an important role in ADHD [4].
The dopamine and norepinephrine pathways control the cognitive control of behavior, motivation and reward perception and thus play a central role in ADHD. Although it is known that gut microbiota can influence levels of neurotransmitters in the body, the precise role of the gut microbiota on these pathways has not been studied [4].
Microbiota can modulate molecules involved in neurogenesis and neuron survival, particularly the brain-derived neurotrophic factor. Levels of this factor are significantly lower in adults with ADHD compared to healthy controls, suggesting that it may be involved in the development of ADHD [5]. Furthermore, in response to dysbiosis, treatment with the probiotic Bifidobacterium longum can normalize levels of the brain-derived neurotrophic factor and restore proper behavior [6].
Perinatal risk factors
The risk of developing ADHD has been associated with several perinatal factors, including delivery mode, gestational age, infant feeding, maternal health and early life stressors [4]. Many of these factors are known to influence the gut microbiota in early life. These links suggest that environmental factors and changes in gut microbial composition can contribute to ADHD.
Several studies, including a meta-analysis, have reported that babies born by C-section have a slightly higher risk of developing ADHD [7, 8]. Babies born by C-section are exposed to and colonized by different microbiota than those born vaginally [9], which may cause downstream effects in development. However, the results linking C-section to ADHD are confounding, and may be due to other factors such as fetal or infant stress.
Preterm babies have higher risk of developing ADHD and suffer more severe symptoms. They seem to lack Bifidobacterium and Lactobacillus, which are two of the main gut bacteria found in healthy infants [10]. As we’ve seen, gut bacteria are involved in many aspects of brain and CNS development, so a gut microbiome that lacks them may not support proper development.
Maternal stress during pregnancy increases the risk of neurodevelopmental disorders, including ADHD and also contributes to more severe ADHD symptoms in offspring [11]. Stress is associated with changes in vaginal bacteria, namely bacterial vaginosis [12]. Stress can also have other detrimental effects on the body and the mother’s microbiome, which may have downstream effects on the microbiome of the offspring.
Additionally, stress in infants (i.e., maternal separation) can cause changes in the microbiome and can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is involved in stress responses and is essential for proper functioning of the gut-brain axis. Activation of the HPA axis produces glucocorticoids or corticosteroids, including cortisol. Children with ADHD have lower levels of cortisol, suggesting HPA dysregulation [13]. Interestingly, supplementation with the probiotic strains Lactobacillus and Bifidobacterium infantis restored the levels of corticosterone and relieved corrected the abnormal HPA response in a mouse model of chronic early life stress [4, 13].
Similar to autism spectrum disorder, maternal infections are also associated with ADHD [14]. Infections during pregnancy can cause maternal immune activation and lead to changes in the gut microbiota, which can affect the brain and behavior of offspring (covered in detail here). As discussed in my post last week, treatment of the offspring with the human gut bacterium Bacteroides fragilis can restore proper brain functioning and behavior in the offspring [15].
Maternal obesity is also linked to the development of ADHD in offspring [4]. Obesity is known to cause systemic inflammation and alterations in the gut microbiota. Dietary interventions while breastfeeding have been shown to reduce the behavioral impact and brain inflammation induced by maternal obesity [16]. However, these results have not been directly linked to changes in the gut microbiota.
Gut microbial composition
I could only find 2 studies that investigated the whole gut microbial composition between individuals with ADHD and healthy controls.
One study looked at 51 children aged 6-10 who had never received treatment for ADHD and compared then to 32 healthy children. They found no differences in the overall structure and diversity of the gut microbiota between healthy children and those with ADHD. They did find that some families of bacteria were increased or decreased in the ADHD group. Particularly, low levels of Faecalibacterium were observed in children with ADHD and were also associated with more severe symptoms [17]. Underrepresentation of Faecalibacterium has also been reported in individuals with atopies such as asthma, eczema and allergic rhinitis, as well as psychiatric diseases, including major depressive disorder and bipolar disorder.
A separate study characterized the microbiota of 19 ADHD and 77 healthy children. This study reported marginally statistically significant differences in the microbiota [18]. However, application of proper statistics methods eliminates the statistical significance, meaning that there was no difference in gut microbiota. One main reason that statistical significance may not have been achieved is the relatively small sample size. The gut microbiota varies substantially between people and minor, yet impactful, differences may not be captured in a group of 19 individuals.
Additional studies including more ADHD patients will be helpful in determining if there are differences in gut microbiota that influence ADHD risk and symptoms. Comparing monozygotic twins who are discordant for ADHD would be ideal.
Dietary interventions and probiotics
Research and anecdotal evidence suggests that diet can play a role in ADHD. As discussed several times on this blog, diet significantly impacts the gut microbiota. A prospective study showed an association between ADHD onset in adolescents and a Western diet high in saturated fat and simple sugars [19].
A systematic review of meta-analyses evaluated three popular dietary interventions used in ADHD. It found that two strategies, eliminating artificial food coloring or supplementing with free fatty acids (omega-3 and omega-6 fatty acids), currently does not have statistically significant support for decreasing ADHD symptoms [20]. However, the restricted elimination diet, or few foods diet, does have a significant effect, possibly offering alternative treatment option for ADHD [20]. Restriction diets eliminate specific foods to which ADHD patients are sensitive or allergic. More studies are needed to understand the effect of these dietary interventions and whether they alter the gut microbiota.
A study of 75 infants showed that treatment with the probiotic Lactobacillus rhamnosus during first 6 months of life reduced the incidence of ADHD at 13 years of age [21]. ADHD or Asperger’s syndrome was diagnosed in 6/35 (17%) of children in the placebo group, whereas no children who received the probiotic were diagnosed. This study measured the levels of several specific gut bacteria in the first 2 years of life and found that some were different first, most notably lower levels of Bifidobacteium longum at 3 and 6 months of age. Interestingly, no changes in the specific gut microbiota they measured were observed at age 13, suggesting that gut microbiota in early life can affect neurodevelopment that is manifested later.
Overall, these studies provide evidence for many factors that may influence the risk of developing ADHD. Although genetics play a strong role, there are several environmental factors over which we may have control, such as staying healthy during pregnancy, avoiding stress during pregnancy and infancy, and cultivating a resilient, diverse microbiota in our babies.
References
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Thapar, A., et al., What have we learnt about the causes of ADHD? J Child Psychol Psychiatry, 2013. 54(1): p. 3-16.
Rogers, G.B., et al., From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry, 2016. 21(6): p. 738-48.
Cenit, M.C., et al., Gut microbiota and attention deficit hyperactivity disorder: new perspectives for a challenging condition. Eur Child Adolesc Psychiatry, 2017. 26(9): p. 1081-1092.
Corominas-Roso, M., et al., Decreased serum levels of brain-derived neurotrophic factor in adults with attention-deficit hyperactivity disorder. Int J Neuropsychopharmacol, 2013. 16(6): p. 1267-1275.
Bercik, P., et al., Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology, 2010. 139(6): p. 2102-2112 e1.
Curran, E.A., et al., Obstetric mode of delivery and attention-deficit/hyperactivity disorder: a sibling-matched study. Int J Epidemiol, 2016. 45(2): p. 532-42.
Curran, E.A., et al., Research review: Birth by caesarean section and development of autism spectrum disorder and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. J Child Psychol Psychiatry, 2015. 56(5): p. 500-8.
Dominguez-Bello, M.G., et al., Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A, 2010. 107(26): p. 11971-5.
Barrett, E., et al., The individual-specific and diverse nature of the preterm infant microbiota. Arch Dis Child Fetal Neonatal Ed, 2013. 98(4): p. F334-40.
Grizenko, N., et al., Relation of maternal stress during pregnancy to symptom severity and response to treatment in children with ADHD. J Psychiatry Neurosci, 2008. 33(1): p. 10-6.
Culhane, J.F., et al., Maternal stress is associated with bacterial vaginosis in human pregnancy. Matern Child Health J, 2001. 5(2): p. 127-34.
Sudo, N., et al., Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol, 2004. 558(Pt 1): p. 263-75.
Silva, D., et al., Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder. Pediatrics, 2014. 133(1): p. e14-22.
Hsiao, E.Y., et al., Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 2013. 155(7): p. 1451-63.
Kang, S.S., et al., Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring. J Neuroinflammation, 2014. 11: p. 156.
Jiang, H.Y., et al., Gut microbiota profiles in treatment-naive children with attention deficit hyperactivity disorder. Behav Brain Res, 2018. 347: p. 408-413.
Aarts, E., et al., Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One, 2017. 12(9): p. e0183509.
Howard, A.L., et al., ADHD is associated with a "Western" dietary pattern in adolescents. J Atten Disord, 2011. 15(5): p. 403-11.
Pelsser, L.M., et al., Diet and ADHD, Reviewing the Evidence: A Systematic Review of Meta-Analyses of Double-Blind Placebo-Controlled Trials Evaluating the Efficacy of Diet Interventions on the Behavior of Children with ADHD. PLoS One, 2017. 12(1): p. e0169277.
Partty, A., et al., A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res, 2015. 77(6): p. 823-8.[if supportFields]><span style='font-size:11.0pt;line-height:115%; font-family:"Calibri","sans-serif";mso-fareast-font-family:Calibri;mso-fareast-theme-font: minor-latin;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language: AR-SA'><span style='mso-element:field-end'></span></span><![endif]